Project 4 aims to explore age-related neurodegeneration from the perspective of one particular neuronal population, namely the locus coeruleus noradrenergic (LC-NE) neurons. This neuronal population deteriorates in the brain during normal aging but also in the brain of Alzheimer's and Parkinson's disease patients. The activity of LC-NE neurons may act as an endogenous protection against insults such as neuroinflammation and oxidative stress. Therefore this project aims to study the role of locus coeruleus in maintaining the overall health of the limbic system and the nigrostriatal system during aging. Since intrinsic vs. extrinsic factors influencing neurodegeneration are difficult to delineate in the intact animal, we propose to utilize intraocular transplants consisting of LC-NE neurons in combination with hippocampal and midbrain nigra dopamine neurons, to examine the specific function of these neurons in aging and age-related neurodegeneration. Intrinsic vs. extrinsic factors will also be examined with blueberry diets (BB) in collaboration with Project 1, to explore the mechanism for its neuroprotective properties. We propose the following two hypotheses for Project 4: 1) LC-NE neurons play a role in protecting other brain regions from oxidative stress and/or inflammation, and age-related degeneration of these neurons leads to secondary damage in the hippocampus, and the midbrain nigra region. 2) Treatment with blueberry extract can reverse age-related degeneration of the LC-NE system, and improve graft survival into the aged host. Based on these hypotheses, we have formulated three aims in which we will explore the relationship between LC-NE innervation and age-related inflammatory and oxidative stress markers. Project 4 will collaborate with Project 1 in terms of blueberry studies, with Project 2 in terms of microglial markers, with Project 3 in terms of the M1/M2 specific markers, and with Project 5 in terms of comparison of protein levels with mRNA expression for critical markers of neurodegeneration with aging.